Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Abstract

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line

“…Since the advent and introduction of tyrosine kinase inhibitors (TKIs), significant improvements have occurred in the treatment of chronic myeloid leukemia (CML), increasing patient’s survival rate [ 1 , 2 , 3 , 4 ]. Although an enormous therapeutic improvement has been demonstrated, there are still some patients that develop treatment resistance mechanisms in the course of disease, making the use with of TKIs ineffective [ 5 , 6 ]. In this scenario, the multidrug resistance (MDR) phenotype is well recognized in clinical practice and continues to be one of the major obstacles in CML treatment, especially in blast crisis [ 7 , 8 , 9 , 10 ].…”

High-Throughput CRISPR Screening in Hematological Neoplasms

“…Although tyrosine kinase inhibitors such as imatinib have been effective to treat CML patients, resistance to this targeted therapy still represents a complex multifactorial process and a challenge for clinicians [ 245 ]. An alternative approach based on the CRISPR-based double knockout (CDKO) system was applied in the CML K-562 cell line to discover novel synergistic drug combinations, highlighting that the dual inhibition of BCL2L1 and MCL1 may be an effective way to combat resistance in CML [ 87 ].…”

Combination of Elacridar with Imatinib Modulates Resistance Associated with Drug Efflux Transporters in Chronic Myeloid Leukemia

“…Regardless of the excellent clinical results of TKIs, such as imatinib, the appearance of resistant cases is raised as a problem in clinical practice [8]. Alterations on the drug target, namely BCR-ABL1 mutations, followed by factors that affect drug pharmacokinetics, are the mechanisms most associated with TKI resistance [9]. Particularly for non-receptor TKIs, such as imatinib, the action of drug efflux pumps is crucial to reaching a therapeutic concentration inside the target cells.…”